Investigation of mechanotransduction mechanism in pulmonary artery for therapeutic application of experimental pulmonary hypertension.

慢性血流动力学增高的血管系统，如高血压和动脉硬化，其致病作用可能部分归因于心血管组织对机械刺激的生物反应。本研究的研究目的是通过对肺动脉机械传导机制的药理学调节，寻找治疗实验性肺动脉高压的新靶点。机械拉伸到初始肌肉长度的180%时，会产生过度的动脉张力，被认为是与肺动脉高压类似的程度。肺动脉牵拉可激活整合素下游信号，这是一种机械感受器；然而，牵拉以依赖整合素的方式(TXA_2和PGF_2α&gt；)和独立的(未转化的)PgH_2、PGE_2和PgI_2的方式增加前列腺素类物质的产生。此外，在这些前列腺素中，ut-PGH_2主要负责牵张引起的肺动脉…的收缩假设PG产生的非整合素途径可能是由分泌型磷脂酶A_2(SPLA2)介导的，我们观察了SPLA2的高选择性抑制剂吲哚沙坦对牵拉引起的肺动脉收缩和UT-PGH_2产生的影响。在正常兔肺动脉上，吲哚青定优先抑制牵张引起的收缩(IC50=0.513μM)，其作用约为乙酰胆碱引起的收缩(IC10.25μM)的20倍。此时，吲哚青定取消了ut-PGH_2的产生。在野百合碱诱导的肺动脉高压大鼠(MCT-PH大鼠)的肺动脉中，X组SPLA2的稳态mRNA水平显著升高。Indoxam(1-3μM)可完全阻断牵拉引起的Ut-PGH_2的节律性收缩和伴随产生的Ut-PGH_2，这是MCT-PH大鼠的一种异常特征。吲哚青能成功阻断正常和病变状态下Ut-PGH_2的产生和肺动脉收缩反应，提示SPLA2有望成为治疗实验性肺动脉高压的新靶点。较少

Pathogenicity of vasculature with chronically increased hemodynamics such as hypertension and arteriosclerosis may be attributable in part to biological responses of cardiovascular tissues against mechanical stimuli. The research purpose of this study is to find a new therapeutic target for experimental pulmonary hypertension through pharmacological regulation of mechanotransduction mechanisms of pulmonary artery.Mechanical stretching to 180% of initial muscle length produces the excessive arterial tension, which is considered to be similar degree in the pulmonary hypertension. The stretching of the pulmonary artery activates downstream signal of integrin, a putative mechanosensor; nevertheless, the stretching augments productions of prostanoids in an integrin-dependent (TXA_2 and PGF_<2α>) and independent (untransformed (ut-)PGH_2, PGE_2, and PGI_2) manner. Of these prostanoids, moreover, the ut-PGH_2 was primarily responsible for the stretch-induced contraction of the pulmonary arter … More y. Assuming that integrin-independent pathway of PG-production might be mediated by secretory phospholipase A_2 (sPLA_2), the effects of indoxam, a highly selective inhibitor for sPLA_2, on the contraction of pulmonary artery and the production of ut-PGH_2 in response to stretching were examined. In a normal rabbit pulmonary artery, indoxam preferentially inhibit the stretch-induced contraction (IC_<50>=0.513 μM), which was about 20-fold more effective than acetylcholine-induced contraction (IC_<50>=10.25 μM). Production of ut-PGH_2 was abolished by indoxam at this time. In the pulmonary arteries of rats with monocrotaline-induced pulmonary hypertension (MCT-PH rats), a significant increase in the steady-state mRNA level for group X sPLA_2 was observed. Indoxam (1-3 μM) completely abolished rhythmic contraction as well as concomitant production of ut-PGH_2 during the prolonged stretching, which is an aberrant character of the pulmonary artery of MCT-PH rats.These results suggest that sPLA_2-mediated production of ut-PGH_2 causes stretch-induced contraction and/or increasing vascular tone of the pulmonary arteries in both normal and the pulmonary hypertension. Successful blockade by Indoxam of ut-PGH_2-production and contractile responses of the pulmonary arteries in both normal and diseased status suggest that sPLA_2 would become a new therapeutic target for experimental pulmonary hypertension. Less